Monoclonal microbial EDP1503 to induce antitumor responses via gut-mediated activation of both innate and adaptive immunity.

Abstract

e14241 Background: Systemic immunity is regulated by interactions of commensal bacteria with immune cells in the gut. Enrichment of specific intestinal microbes has been shown to enhance the anti-tumor response to PD-1 blockade in both murine models and cancer patients. Here we report that oral administration of a monoclonal microbial, EDP1503, induces systemic anti-tumor immunity. Methods: The mechanism of action and efficacy of EDP1503 was investigated in isograft tumor models and a variety of ex vivo and in vitro studies in murine and human cells. Results: EDP1503 increases expression of costimulatory molecules on CD11c+ dendritic cells (DCs) within the mesenteric LNs with an accompanying increase in proinflammatory CD103+ DCs within tumor draining lymph nodes. In addition, EDP1503 amplifies both myeloid and lymphocyte responses via production of DC-derived growth factors, M1 polarization of macrophages, and production of the lymphocyte-recruiting chemokines, CXCL9 and CXCL10. Mechanistically, EDP1503 triggers specific pattern recognition receptors and induces proinflammatory responses in antigen presenting cells. Moreover, in vivo, treatment of mice with EDP1503 results in decreased tumor volume and delayed tumor growth. The prominent anti-tumor effects of EDP1503 are further augmented by combination with anti-PD-1 neutralizing Abs. Dissection of the tumor microenvironment reveals increased activated Ki67+ NK cells and CD8+ T cells producing IFNg. Conclusions: Together, these data clearly demonstrate the ability of an orally delivered non-colonizing monoclonal microbe to enhance innate and adaptive anti-tumor immunity and substantiates the rationale for ongoing clinical trials. EDP1503 is currently in Phase 1b/2 studies (NCT03775850; NCT03595683) with enrollment open at multiple sites.